Inflammation Mechanisms in Acute Kidney Injury

Acute kidney injury (AKI) is characterised by a rapid reduction in glomerular filtration rate and accumulation of nitrogenous waste. Central to its pathogenesis is a dysregulated inflammatory response triggered by ischaemia, nephrotoxins or sepsis. Injury to tubular epithelial and endothelial cells releases damage-associated molecular patterns that activate pattern recognition receptors on resident dendritic cells and recruited neutrophils and monocytes. These cells secrete pro-inflammatory cytokines and chemokines, leading to further immune‐cell infiltration, reactive oxygen species (ROS) production and activation of nuclear factor-κB and inflammasomes. Neutrophils and pro-inflammatory macrophages promote tubular cell apoptosis and microvascular injury, exacerbating ischaemia. Resolution requires a switch to anti-inflammatory mediators, engagement of autophagy and mitophagy pathways, and restoration of endothelial integrity. Failure of resolution programmes can precipitate chronic inflammation, fibrosis and progression to chronic kidney disease.

Research from Nature Portfolio

Recent studies have delineated a novel YY1–KIM1–DR5 axis in the tubular epithelium, in which down-regulation of the transcription factor YY1 during AKI permits overexpression of kidney injury molecule-1 (KIM1). KIM1 engages death receptor 5 (DR5) to trigger a caspase-dependent apoptotic cascade, amplifying epithelial loss. Rationally designed peptides that block the KIM1–DR5 interaction confer reno-protective effects in preclinical models. In addition, work on the natural anthraquinone rhein has shown that it attenuates endotoxin-induced AKI by suppressing NF-κB activation, reducing macrophage infiltration and lowering levels of pro-inflammatory cytokines and chemokines in the injured kidney.

Inflammation Mechanisms in Acute Kidney Injury publication trend

The graph below shows the total number of articles in inflammation mechanisms in acute kidney injury across all publications each year (not limited to Nature Index journals).

Technical terms

Acute kidney injury (AKI): A rapid decline in renal function leading to retention of waste products and electrolyte imbalance.

Cytokines: Small signalling proteins that modulate immune and inflammatory responses.

Chemokines: A subclass of cytokines that direct the migration of immune cells to sites of tissue injury.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage cells and amplify inflammation.

Apoptosis: Programmed cell death involving caspase activation and controlled cellular disassembly.

Transcription factor: A protein that binds specific DNA sequences to regulate gene expression.

DNA demethylation: The removal of methyl groups from DNA cytosine residues, often leading to increased gene transcription.

Mitophagy: Selective autophagic removal of damaged mitochondria to maintain cellular homeostasis.

Nrf2: A transcription factor that induces antioxidant and cytoprotective gene expression.

STAT3: Signal transducer and activator of transcription 3, a mediator of cytokine signalling involved in cell survival and inflammation.

KIM1: Kidney injury molecule-1, a transmembrane protein upregulated in injured renal tubular epithelial cells.

DR5: Death receptor 5, a cell-surface receptor that triggers apoptosis upon ligand binding.

References

1. A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury. Nature Communications (2023).
2. Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase. Theranostics (2023).
3. 4-Octyl itaconate attenuates LPS-induced acute kidney injury by activating Nrf2 and inhibiting STAT3 signaling. Molecular Medicine (2023).
4. Rhein prevents endotoxin-induced acute kidney injury by inhibiting NF-κB activities. Scientific Reports (2015).